1. Field of the Invention
The invention relates to pharmaceutical preparations with cardiac, particularly antiarrhythmic, activity.
2. Description of the Prior Art
Some diuretic and anti-hypertensive triaminoarylpteridine compounds are disclosed in U.S. Pat. No. 3,081,230. Among these, 2,4,7-Triamino-6-phenylpteridine and certain of its derivatives have shown the greatest activity in this area. Thus 2,4,7-triamino-6-phenylpteridine, under the name triamterene, has acquired major therapeutic importance due to its anti-kaliuretic action.
The general disclosure in U.S. Pat. No. 3,081,230 provides substituents on the para-position of the phenyl ring situated on the 6-position of the pteridine molecule. These substituents include alkyl and alkoxy groups containing up to 3 carbon atoms, a trifluoromethyl group or a halogen atom.
More specifically, the p-chloro-, p-trifluoromethyl- and p-fluorophenyl compounds are described in this U.S. patent.
U.S. Pat. No. 3,081,230, however, contains no further data on the pharmaceutical applicability of these compounds.
The present inventors have conducted a broadly based scientific study which yielded over a hundred structure activity relations for pteridine derivatives (J. Weinstock et al., J. Med. Chem. (1968) 11:573-579; "Therapie mit Triamteren", 1966, in: Wiener Symposium, chaired by K. Fellinger, pub. Georg Thieme Verlag, Stuttgart, 1968.)
The present inventors summarized their results regarding the effects of substitutions on the phenyl group as follows: "In Table VIII is shown the diuretic activity of compounds in which the phenyl of triamterene has been replaced by a substituted phenyl. Here again, only small changes are permissible if even modest diuretic activity is to be retained". (Weinstock et al., loc. cit., p. 578.)
In fact, the data appears to support the hypothesis that neither hydrophilic substitution, e.g. --OH, --NH or ##STR2## nor lipophilic substitution, e.g. CH.sub.3 --, F-- or C.sub.6 H.sub.5 -- in the para position of the phenyl group leads to pharmaceutically valuable compounds.
Further study has shown that hydrophilic substitution does not eliminate diuretic and anti-kaliuretic activity for triamterene derivatives.
Thus, it has been surprising discovered that, in equimolar concentrations, the triamterene metabolites p-hydroxytriamterene (phase I metabolite) and hydroxytriamterene sulfuric acid ester (phase II metabolite) have practically the same activity for electrolyte transport as triamterene itself. (H. Knauf et al., Arzneim.-Forsch./Drug Res. (1978) 28, (II):1417-1420; U.S. Pat. No. 4,118,492.)
High diuretic, anti-kaliuretic, anti-hypertensive, and cardioprotective activity is known for derivatives of p-hydroxytriamterene with pronounced hydrophilic substitution (See British Pat. No. 2,018,133).
According to the prior art, however, non-hydrophilic substituted derivatives of triamterene do not appear to have any recognizable therapeutic potential. Moreover, there was the generally recognized latent hazard that these pteridine derivatives would have folic acid antagonist properties, which are not possessed by triamterene itself to any appreciable degree (see Fellinger, loc. cit.).
Triamterene and its therapeutically recommended derivatives are a well studied class of substances with relatively insignificant side effects. These compounds are also easy to study analytically.
It is well known that cardiac disorders are responsible for a large percentage of the causes of death in industrial countries. In particular, cardiac arrhythmias play a significant role in these fatal disorders. Pathological changes in heartbeat frequency are generally attributable to disturbances in the formation or conduction of the excitation phase of the heart beat. Depending on the type of disturbances present (e.g., bradycardia, tachycardia, or arrythmia) the medication employed (anti-arrhythmic or anti-fibrillatory) will be such as to accelerate the heartbeat, to decelerate the heartbeat, or to eliminate irregularities.
Examples of frequently used anti-fibrillatory substances are:
(i) quinidine (a diastereomer of quinine); PA1 (ii) the rauwolfia alkaloid ajmaline; PA1 (iii) the coronary therapeutic agent verapamil; PA1 (iv) the local anesthetics procainamide and lidocaine; PA1 (v) the anti-epileptic phenytoin; and PA1 (vi) beta-blocking agents. PA1 (2) an alkyl group having 1 to 6 carbon atoms, and which may be a linear, a branched or a cyclic alkyl group which is either saturated or unsaturated; branched and cyclic alkyl groups are preferred; PA1 (3) a benzyl group; PA1 (4) a trifluoromethyl group; or PA1 (5) a nitro group.
As is seen, these are substances with markedly different chemical structures.
In general anti-fibrillatory activity is connected with a reduction of excitation formation and excitation conduction in the cells of a specific excitation conduction system and of the working myocardium. The anti-fibrillatories, as a rule, act negatively inotropically. Therefore, in general they are contraindicated in cases of cardiac insufficiency. Moreover, the alkaloids and other substances mentioned above are often not well tolerated and/or generate allergic reactions with patients undergoing treatment.
Accordingly, there is a persistent need for a new anti-arrhythmic substance.